Septic shock is a systemic inflammatory response syndrome that causes multiple organ damage and death. Currently, there is no efficient treatment for the disease. Identifying novel therapeutic targets that can help control sepsis-induced inflammation is crucial to treat this devastating disease. Activation of complex inflammatory networks is responsible for the excessive systemic inflammatory response in sepsis. NF-kB has been demonstrated as a central player that regulates these inflammatory networks in sepsis. However, molecular regulation of NF-kB activity in sepsis remains largely unknown. Recent studies indicate that acetylation is a new mechanism in NF-kB activation. It has been reported that Sirt1, a deacetylase widely expressed in all tissues, interacts with NF-kB and inhibits NF-kB activity by deacetylation in several in vitro and in vivo systems. Yet, the function and regulation of Sirt1 in sepsis-induced inflammatory responses have not been studied. Using mouse models of sepsis, we demonstrate that Sirt1 controls inflammatory responses during sepsis by regulating NF-kB acetylation and activation. Our preliminary data showed that induction of sepsis triggered NF-kB acetylation and activation in wild type mice, which were further increased in Sirt1 knockout mice. Interestingly, Sirt1 activation by resveratrol or Sirt1 gene delivery inhibited sepsis-induced NF-kB acetylation. Furthermore, we showed that caspase activation resulted in Sirt1 degradation, which may function as a new pathway to aggravate systemic inflammation in sepsis. In the proposed studies, we will test the hypothesis that Sirt1 controls NF-k B activation and inflammatory responses during sepsis. Our specific aims are: (1) to define the role of Sirt1 in sepsis-induced NF-kB activation and systemic inflammation. We will use inducible Sirt1 knockout mice to assess the role of Sirt1 in sepsis-induced systemic inflammation; we will examine the role of caspase in Sirt1 regulation of NF-kB activation and inflammatory signaling during sepsis; (2) to specifically dissect Sirt1 control of NF-kB activation in endothelial cell inflammatory responses during sepsis. We will define Sirt1 control of sepsis-induced NF-kB activation and inflammatory signaling in endothelial cells. We will use endothelial-specific Sirt1 knockout mice to assess the role of endothelial Sirt1 in NF-kB modulation and inflammatory signaling in sepsis; (3) to explore the therapeutic potential of modulating NF-kB activation by Sirt1 activators and Sirt1 gene delivery in sepsis-induced inflammation. We will explore the therapeutic potential of Sirt1 activators on sepsis-induced NF-kB activation and inflammatory signaling; we will evaluate whether Sirt1 gene delivery can effectively protect against sepsis-induced inflammation by inhibiting NF-kB-regulated inflammatory signaling. Successful completion of the proposed studies will disclose Sirt1 as a novel modulator of sepsis-induced NF-kB activation and inflammation, and validate the potential of Sirt1 as a therapeutic target to treat sepsis-associated inflammatory tissue damage.